Alzheimer disease (AD) impairs memory and causes cognitive and psychiatric deficits. Over 35 million people throughout the world are afflicted, including 5.4 million in the USA. All AD cases are marked by the accumulation of two lesions in the brain called plaques (consisting of a protein called A?) and tangles (consisting of a protein called tau that becomes hyperphosphorylated. One of the most fundamental and unresolved questions in the field centers around elucidating the relationship between A? and tau and their role in cognitive decline. It is critical to determine if A? triggers pathology in human wild-type au, rather than the mutant used in previous models. Moreover, this proposal seeks to identify the interactions between these two critical proteins at the synapse using synaptoneurosomes, thereby enabling us to quantify A? and tau levels in the synapse and other key markers of synaptic function. Lastly, the broad goal of this application is to understand how these synaptic changes lead to cognitive deficits, and whether therapies that remove either A? or tau alone are sufficient to improve behavior. It is important to point out that research in the AD field can only progress if the tools evolve, hence there is an urgent need to develop and characterize new animal models until an effective treatment is discovered. Because the 3xTg-AD mice harbor mutant tau, addressing these issues necessitated the generation of innovative new transgenic models and viral vectors to manipulate gene expression in vivo. The first novel model we developed is a floxed human APP transgenic mouse that permits ablation of APP expression using Cre recombinase. We also created a novel human wild-type tau transgenic model that develops phosphotau pathology. After crossing these two lines, we can discover the impact A? has on the development of tau pathology during various stages (i.e., before, during, and after tau pathology is established). Results from this study will reveal the conditions under which A? induces wild-type tau pathology. Additionally, we will be uniquely positioned to determine if tau pathology continues to cause synaptic deficits even if A? is suppressed using Cre. Using viral gene delivery to the CNS, we will determine whether intracellular and extracellular A? plays a greater role in modulating tau pathology and cognitive decline. The development of the floxed human APP transgenic mice represents a significant advance for the field, as it enables abrogation of human APP gene expression using viral delivery of Cre recombinase during temporally-specified timepoints. Utilizing these novel models and innovative genetic approaches that add significantly to the research tool armatorium, we will unravel the distinctions between the cognitive loss due to A?-dependent and -independent mechanisms, the pathological time point of A?-induced tau dysfunction, and whether the presence of A? intracellularly or extracellularly facilitates tau pathology and cognitive decline. Because a better understanding of these pathways is critical not only for academic reasons but also for helping to identify novel drug targets, the translational impact of this work is substantial and significant.